Adenosine is a well-known component of several endogenous molecules (ATP, NAD+, nucleic acids). It plays an important regulatory role in many physiological processes. The effect of adenosine on the heart function was described already in 1929 (Drury and Szentgyörgyi, Physiol. 68:213, 1929). The identification of an increasing number of physiological functions mediated by adenosine and the discovery of new adenosine receptor subtypes are offering possibilities for the therapeutic application of specific ligands (Poulse, S. A. and Quinn, R. J. Bioorganic and Medicinal Chemistry 6:619, 1998).
To date, the receptors for adenosine have been classified into three main classes: A1, A2 and A3. The A1 subtype is partly responsible for the inhibition of the adenylate cyclase by coupling to Gi membrane protein, and partly influences other second messenger systems. The A2 receptor subtype can be subdivided into two further subtypes—A2a and A2b—which stimulate the adenylate cyclase activity. The sequence of the adenosine A3 receptors have been first identified from rat testis cDNA library. Later it was proved that it corresponds to a novel, functional adenosine receptor. The activation of the A3 receptors is also connected with several second-messenger systems: inhibiting of adenylate cyclase, stimulating phospholipase C and D.
The adenosine receptors are found in several organs and regulate their functions. Both A1 and A2a receptors play important role in the central nervous system and cardiovascular system. In the CNS, the adenosine inhibits the release of synaptic transmitters which effect is mediated by A1 receptors. In the heart, the A1 receptors also mediate the negative inotropic, chronotropic and dromotropic effects of adenosine. The adenosine A2a receptors, which are located in a relatively high amount in the striatum, display functional interaction with the dopamine receptors in regulating the synaptic transmission. The A2a adenosine receptors on endothelial and smooth muscle cells are responsible for adenosine-induced vasodilation.
On the basis of RNA identification, the A2b adenosine receptors are widely distributed in different tissues. They have been identified in almost every cell type, but its expression is the highest in the intestine and the bladder. This subtype probably also has important regulatory function in the regulation of the vascular tone and plays a role in the function of mast cells.
Contrary to A1 and A2a receptors, where the tissue distribution was detected on the protein level, the presence of A2b and A3 receptors was detected on the basis of their mRNA level. Expression levels for A3 adenosine receptors are rather low compared to other subtypes and they are highly species dependent. A3 adenosine receptors are expressed primarily in the central nervous system, in the testis and in the immune system, and appear to be involved in the modulation of the mediator release from the mast cells in immediate hypersensitivity reaction.
For therapeutic use, it is essential to ensure that the molecule does not bind, or binds only in the case of very high concentration to the A1, A2a and A2b sub-types of the adenosine receptor.
A3 antagonists published so far in the literature, belong to the groups of flavonoides, 1,4-dihydropyridine derivatives, triazoloquinazolines, thiazolonaphthyridines and thiazolopyrimidines. Most of the effective and for the adenosine subtypes selective antagonists, however posses strong lipophilic character, and they are therefore sparingly soluble in water. This feature hinders the in vivo applicability of the compounds. In the literature more and more studies are to find aiming the preparation of water-soluble adenosine A3 receptor antagonists (Ch. E. Müller et al., J. Med. Chem. 45:3440, 2002; A. Maconi et al., J. Med. Chem. 45:3579, 2002).
Patent application WO 02/096879 discloses 2-amino-3-cyanoquinoline derivatives as structurally novel type, effective A3 antagonists. The compounds described in patent application WO 02/096879 are A3 antagonists with high selectivity of the following general formula:
    R1′ stands for hydrogen atom or straight or branched C1-4 alkyl group;    R2′ stands for hydrogen atom or straight or branched C1-4 alkyl group;    R3′ stands for hydrogen atom or straight or branched C1-4 alkyl group, phenyl, thienyl, or furyl group, optionally substituted with one or more straight or branched C1-4 alkyl group, straight or branched C1-4 alkoxy group or halogen atom; a six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulphur atom, optionally substituted with one or more straight or branched C1-4 alkyl group, straight or branched C1-4 alkoxy group or halogen atom;    R9′, R10′, R11′, and R12′ independently stand for hydrogen atom, straight or branched C1-4 alkyl group, straight or branched C1-4 alkoxy group, hydroxy group or halogen atom, or R9′ and R12′ stand for hydrogen atom and R10′ and R11′ form together a methylenedioxy group;    R6′ stands for hydrogen atom or a cyano group, aminocarbonyl group, C1-4 alkoxycarbonyl group, or carboxy group;    R7′ stands for hydrogen atom or straight or branched C1-4 alkyl group, phenyl, benzyl, thienyl, or furyl group, optionally substituted with methylenedioxy-group or with one or more straight or branched C1-4 alkyl group, straight or branched C1-4 alkoxy group, hydroxy group, trifluoromethyl group, cyano group or halogen atom; or a six- or five-membered heteroaromatic ring containing one, two or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulphur atom, optionally substituted with one or more straight or branched C1-4 alkyl group, straight or branched C1-4 alkoxy group or halogen atom;    X′ stands for —CH2— group, —NH— group, —NR8′— group, or sulphur atom, oxygen atom, sulpho group or sulphoxy group, wherein R8′ stands for straight or branched C1-4 alkyl group or C3-6 cycloalkyl group;    n′ represents zero, 1 or 2;
These compounds too, have the characteristic disadvantage that they are only sparingly soluble, which hampers their development into a drug. What would be useful would be compounds having solubility profiles that are far better than those of the known 2-amino-3-cyanoquinolines, besides, and which would also be highly active.